Generic antidepressants / Les antidépresseurs génériques

To control the rising costs of prescription medications, cash-strapped provincial drug plans and cost-conscious insurance companies are turning to mandatory generic substitution. Could these rules affect the safety, efficacy and availability of prescription drugs your patients rely on?

Bioequivalence ambivalence

Generic drugs have the same chemical structure, strength, dosage form and route of administration as their brand-name counterparts. However, they may have different non-medicinal ingredients, such as fillers, colouring agents and preservatives, as well as different shapes, colours or markings, from the originals.

For physicians, of course, the key issues are safety and efficacy. These properties are gauged through bioequivalence: if a generic product shows the same rate and extent of absorption in the body, or bioavailability, as the innovator drug, there probably won’t be any clinically significant differences. To be accepted as bioequivalent, a generic product must meet both of the following criteria:1
• maximum blood concentration (Cmax): 80%–125% of reference
• area under the curve (AUC; a measure of total drug exposure over time): 90% confidence interval (CI) 80%–125% of reference

This means an absolute variance of less than 5% between products — not the 45% difference between 80% and 125%, as some claim.1 In over 2000 generic drugs approved by the US Food and Drug Administration (FDA), average differences were 4.35% for Cmax and 3.56% for AUC.2 That’s well within the 5% batch-to-batch variation permitted for individual products.3

However, even relatively small variations in dose or concentration can have serious consequences for a small group of drugs that are highly toxic or have a narrow therapeutic range. Known as critical dose drugs, Health Canada has stricter bioequivalence standards for their generic versions.4 The only critical dose drug used in depression is lithium,1 an add-on option for resistant depression.5

Another concern is patients with allergies or intolerances to fillers, such as lactose, gluten, sulfites and tartrazine, but drug excipients can be checked in the Compendium of Pharmaceuticals and Specialties.6

Some patients — and physicians — may still have doubts about the clinical equivalence of generic drugs. Case reports and observational studies have suggested adverse outcomes from generic substitution of various drugs, including psychotropics,7 but high-quality, well-controlled studies in many therapeutic classes generally haven’t found any differences.8

Quality questions

Generic drug manufacturers have to follow the same strict federal manufacturing guidelines — enforced by regular inspections — as innovator companies. Violations posing a risk to safety are subject to immediate corrective measures, including recalls, public advisories, border restrictions and even license suspension or termination.9

And since about 80% of medications used in Canada are imports, these regulations apply equally to foreign manufacturers. Recently, Health Canada stopped imports of drugs and drug ingredients from several factories in China and India due to “data integrity concerns,” from sloppy record-keeping to outright fraud,10 but companies in other countries, including the US, UK and Italy, have also been flagged for problems.11

Drug recalls and warnings in Canada tripled during 2005¬–13 (from 42 to 143), mainly due to stability and contamination issues. The majority involved generic manufacturers, but innovator companies were also affected.12

Drug bans and recalls can cause or worsen drug shortages, which in turn may force pharmacies to switch patients from one generic to another, or even from brand name to generic versions.

No more no subs?

If a brand-name medication has a generic equivalent, most provincial and private drug plans will usually only cover the generic cost. Pharmacists aren’t legally required to inform patients or doctors of a generic substitution, but they’re generally encouraged to tell patients, who may keep the brand-name version if they’re willing to pay the difference. Insurers are also cracking down on “No substitution” prescriptions, requiring them to be handwritten and documented as medically necessary.13

To avoid misunderstandings, nonadherence, and unexpected adverse events or treatment failures, prepare patients for the possibility of generic substitution, and encourage them to tell you if they’ve been switched. If you can confidently reassure them that generic drugs work just as well as brand-name ones, you’re far more likely to achieve successful treatment.